35MO - Number of IL-2 doses and clinical outcomes of tumor-infiltrating lymphocyte (TIL) cell therapy: Post hoc analysis of the C-144-01 trial of lifileucel in patients with advanced melanoma

Background

Aldesleukin (IL-2), at high doses in repeat cycles, is approved as monotherapy for patients (pts) with metastatic melanoma. Its limited efficacy is mediated through endogenous T cell activation, which also contributes to considerable toxicity (Rosenberg NEJM 1988). Lifileucel, a one-time investigational TIL cell therapy, showed a 31% IRC-assessed objective response rate (ORR) in 153 pts with advanced melanoma who progressed after immune checkpoint inhibitors and targeted therapy (if BRAF mutation positive) in the phase 2 C-144-01 trial (Sarnaik SITC 2022) using abbreviated high-dose IL-2 (≤6 doses) with 79% lower potential maximum cumulative exposure than monotherapy. Prior studies found no association between IL-2 dosing and TIL cell therapy efficacy (Goff JCO 2016, Seitter CCR 2021). This post hoc analysis explores the association between number of IL-2 doses and clinical outcomes of lifileucel.

Methods

Pts with advanced melanoma received cyclophosphamide and fludarabine (NMA-LD, Day –7 to –1), a single lifileucel infusion (Day 0), and ≤6 IL-2 doses (600,000 IU/kg) every 8–12 h (Day 0–4). Per protocol, IL-2 was discontinued based on physiologic tolerance. The association between number of IL-2 doses administered and ORR (RECIST v1.1 per IRC) and duration of response (DOR) was explored.

Results

In 153 pts who received lifileucel, median number of IL-2 doses was 6 (1–2 doses: n=16; 3–4 doses: n=26; 5–6 doses: n=109; 2 pts did not receive IL-2). All pts developed G3/4 lymphopenia (per lab values) after NMA-LD (Day 0–4). ORR to lifileucel was 38%, 31%, and 31% in pts receiving 1–2, 3–4, and 5–6 doses, respectively (p=0.87); 67%, 75%, and 47% of responders had DOR ≥12 mo (Cox regression p=0.39). ORR was 40% in 5 pts who progressed after prior high-dose IL-2 monotherapy.

Conclusions

Lifileucel ORR and DOR were not associated with number of IL-2 doses administered. Pts with disease refractory to prior IL-2 monotherapy derived benefit from lifileucel. Presence of G3/4 lymphopenia in all pts at time of IL-2 administration argues against a direct antineoplastic effect of abbreviated IL-2 dosing as part of the lifileucel regimen.

Clinical trial identification

NCT02360579.

Editorial acknowledgement

Medical writing support was provided by Jayasri Srinivasan and Swati Ghatpande of Second City Science, a Vaniam Group Company.

Legal entity responsible for the study

Iovance Biotherapeutics, Inc.

Funding

Iovance Biotherapeutics, Inc.

Disclosure

J.C. Hassel: Financial Interests, Personal, Other, Honoraria: Almirall, Amgen, Novartis, Roche; Financial Interests, Personal, Other, Honoraria, Research Funding: BMS, Sanofi; Financial Interests, Personal, Other, Honoraria, Consulting Or Advisory Role: GSK, MSD, Pierre Fabre; Financial Interests, Personal, Other, Honoraria, Research Funding, Consulting Or Advisory Role, Travel, Accommodations, Expenses: Sunpharma. A. Sarnaik: Financial Interests, Personal, Other, Research Funding, Patents, Royalties, Other Intellectual Property: Provectus; Financial Interests, Personal, Other, Consulting Or Advisory Role, Research Funding, Travel, Accommodations, Expenses, Patents, Royalties, Other Intellectual Property: Iovance; Financial Interests, Personal, Other, Honoraria: Physicians' Educational Resource, Medscape, Medstar Health; Financial Interests, Personal, Other, Consulting Or Advisory Role: Guidepoint, Defined Health, Huron Consulting Group, Keyquest, Istari, Gerson Lehrman Group. J. Chesney: Financial Interests, Personal, Other, Consulting Or Advisory Role, Research Funding: Amgen; Financial Interests, Personal, Other, Research Funding: Replimune, Iovance, FATE. T. Medina: Financial Interests, Personal, Advisory Role, consulting: Pfizer, Taiga, Merck, Bristol Myers Squibb, Iovance, Moderna, Nektar, Regeneron, Exicure, Checkmate, BioAtla, Xencor, Replimune, Day One Pharmaceutical. O. Hamid: Financial Interests, Personal, Other, consulting or advisory role, speaker bureau: BMS, Sanofi Regeneron, Novartis, Pfizer; Financial Interests, Personal, Other, speaker bureau: Novartis, Pfizer; Financial Interests, Personal, Other, consulting or advisory role: Aduro, Akeso, Alkermes, Beigene, Bioatla, Roche Genentech, GlaxoSmithKine, Immunocore, Idera, Incyte, InstilBio, Iovance, Janssen, Merck, Nextcure, Seattle Genetics, Tempus, Zelluna; Financial Interests, Institutional, Other, contracted research (for institution): Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, CytomX, Exelixis, Roche Genentech, GlaxoSmithKline, Immunocore, Idera, Incyte, Iovance, Merck, Moderna, Merck-Serono, NextCure, Novartis, Pfizer, Rubius, Sanofi/Regeneron, Seattle Genetics, Taiga, Torque, Zelluna. S. Thomas: Financial Interests, Personal, Other, Research Funding, Consulting Or Advisory Role, Travel, Accommodations, Expenses, Honoraria, Speaker’s Bureau: BMS, Merck, Pfizer, Ipsen, Amgen, Genentech, Foundation One. M. Wermke: Financial Interests, Personal, Other, Honoraria, Consulting or Advisory Role: Novartis, Lilly; Financial Interests, Personal, Other, Honoraria, Consulting or Advisory Role, Travel, Accommodations, Expenses: Pfizer; Financial Interests, Personal, Other, Honoraria, Consulting or Advisory Role, Research Funding, Travel, Accommodations, Expenses: Roche; Financial Interests, Personal, Other, Consulting or Advisory Role, Travel, Accommodations, Expenses: Bristol Myers Squibb, GEMoaB, AstraZeneca, Amgen; Financial Interests, Personal, Other, Consulting or Advisory Role: Cellex GmbH, Boehringer Ingelheim, ISA Pharmaceuticals, MSD, Immatics. E. Domingo-Musibay: Financial Interests, Personal, Other, Speaker’s Bureau, Consulting Or Advisory Role: Regeneron; Financial Interests, Personal, Other, Honoraria: Castle Biosciences; Financial Interests, Personal, Other, Research Funding: Clinigen. J.M. Kirkwood: Financial Interests, Personal, Other, Consulting/SAB: Amgen, Inc., Ankyra Therapeutics, Applied Clinical Intelligence, Llc, Axio Research, Llc, Becker Pharmaceutical Consulting, Bristol Myers Squibb, Cancer Network, Checkmate Pharmaceuticals, DermTech, Fenix Group International, Harbour BioMed, Immunocore Llc, Iovance Biotherapeutics, IQVIA, Istari Oncology, Merck, Natera, Inc., Novartis Pharmaceuticals, OncoCyte Corporation, OncoSec Medical Inc., Pfizer, Inc., Replimune, Inc., Scopus BioPharma, Inc., SR One Capital Management, LP, Takeda Development Center Americas, Inc., Takeda Pharmaceutical Company Limited; Financial Interests, Institutional, Other, Research Trial Support to Institution: Amgen, Inc., Bristol Myers Squibb, Checkmate Pharmaceuticals, Harbour BioMed, Immvira Pharma Co., Immunocore Llc, Iovance Biotherapeutics, Novartis Pharmaceuticals, Takeda, Verastem, Inc. J. Larkin: Financial Interests, Personal, Other, Honoraria: Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Royalo Collge of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMS; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pierre Fabre, Roche, GSK; Financial Interests, Personal, Other, Consulting Or Advisory Role: iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte ; Financial Interests, Personal, Other, Research Funding: BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, Aveo. J.S. Weber: Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: Named on CTLA4 biomarker patent and a TIL growth patent by Moffitt Cancer Center and a PD-1 biomarker patent by Biodesix; Financial Interests, Personal, Stocks/Shares: Biond, Instil Bio, OncoC4, Evaxion; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: BMS; Financial Interests, Personal, Other, Honoraria, Consulting Or Advisory Role: BMS, Merck, GSK, Pfizer, Sellas, Biond, OncoC4, ImCheck, Genentech, AstraZeneca, Regeneron, Instil Bio, Iovance, Evaxion, Ultimovacs; Financial Interests, Personal, Other, Research Funding: BMS, Moderna, Merck, Incyte, Genentech. A.M. Arance Fernandez: Financial Interests, Personal, Invited Speaker, Speaker’s Bureau: BMS, Roche, Novartis, Pierre Fabre, MSD, Merck, Sanofi; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: BMS, MSD, Novartis, Pierre Fabre; Financial Interests, Personal, Other, Consulting Or Advisory Role: BMS, Roche, Novartis, Pierre Fabre, MSD, Merck, Sanofi; Financial Interests, Personal, Other, Research Funding: Pierre Fabre, Novartis, Roche, BMS, MSD, Merck, Sanofi. J.F. Rodriguez: Financial Interests, Personal, Other, Employment: HM Hospitales; Financial Interests, Personal, Other, Advisory boards and Consul∖ng: BMS, Amgen, Novartis, Rainier, Janssen, Pierre-Fabre; Financial Interests, Personal, Other, Speaker honoraria: Roche, BMS, Novartis, MSD, Janssen, Pfizer, AstraZeneca, EUSA-Pharma, Astellas, Bayer; Financial Interests, Personal, Other, Travel, accommodations, expenses: Astellas, Novartis, Roche, BMS, Pfizer, MSD, Pierre-Fabre; Financial Interests, Personal, Other, Corporate-sponsored research: AstraZeneca, BMS, Amgen, Roche, Novartis, MSD, Janssen, Pfizer, Astellas, GSK, PharmaMar, Ipsen, Tesaro, AbbVie, Aprea Therapeutics, Eisai, Bayer, Merck. I. Thomas: Financial Interests, Personal, Other, Congress and travel expenses: AbbVie, Roche, Sanofi; Financial Interests, Personal, Other, Honoria and travel expenses for talks: Pierre Fabre; Financial Interests, Personal, Other, Honoraria for advisory board: BMS; Financial Interests, Institutional, Other, Research funds (ins]tu]onal): BMS, Pfizer, MSD, Amgen, Argn-X, Leo, Novartis, UCB, 4SC, AstraZeneca, Biontech, Genentech, Roche, Biotech, Curevac, Huya, Incyte, Idera, Iovance, Infla-Rx, Cerpass, Kartos, Nektar, Philogen, Pierre Fabre, Regeneron, Replimune, Sanofi. P.G. Corrie: Financial Interests, Personal, Other, advisory board and speaker honoraria: BMS, MSD, Pierre Fabre, Novartis; Financial Interests, Personal, Other, consultancy: Microbiotica; Financial Interests, Personal, Other, travel & accommodation: MSD; Financial Interests, Institutional, Other, research funding to institution: Pierre Fabre, MSD. V. Gontcharova: Financial Interests, Personal, Other, Current Employment, Current Equity Holder in publicly-traded company, Travel, Accommodations, Expenses (paid by any for-profit health care company): Iovance Biotherapeutics; Financial Interests, Personal, Other, Current Equity Holder in publicly-traded company: Gilead, Meta, Intel. X. Wu, W. Shi: Financial Interests, Personal, Other, employment with and stock or other ownership: Iovance Biotherapeutics. H. Kluger: Financial Interests, Personal, Other, Consulting Or Advisory Role: Bristol Myers Squibb, Clinigen, Shionogi, Chemocentryx, Calithera, Signatero, Gigagen, GI reviewers, Merck; Financial Interests, Personal, Other, Research Funding: Apexigen, Bristol Myers Squibb, Merck.